Drug treatment of peripheral arterial disease

Bandolier
is always interested to hear about interventions that don't work. If the
evidence is strong, then we can drop the intervention and get on with thinking
about things that do work. So when we were told that a drug treatment for
treatment of peripheral artery disease was ineffective, we sought the evidence.

Background

Risk factors for peripheral artery disease are much the same as for
cardiovascular or cerebrovascular disease. They are age, smoking, hypertension,
hyperlipidaemia, diabetes, obesity, physical inactivity and family history. Of
these, by far the most important is cigarette smoking; the relative risk is about
9 for those smoking more than 15 cigarettes a day.

Peripheral artery disease produces symptoms of pain, ache, cramp or severe
fatigue in one or both legs occasioned by walking (intermittent claudication), so
that those affected slacken their walking pace, or stop altogether. Pain-free
walking distance (PFWD) on a treadmill at standard pace and incline is one of the
tests used in determining disease severity.

Surgical treatments

In the 20-30% of patients who experience progressive deterioration, surgical
treatments may include arterial grafts to remove the blockage in the peripheral
arteries. Blockages tend to occur in large arteries with a high pressure, and at
the bifurcation of arteries. In extreme cases (3-6%) amputation of the affected
limb may be necessary [1].

Surgical treatments are expensive. In a paper examining the lack of information
on the cost-effectiveness of drug treatments, Drummond & Davies from the
Centre for Health Economics at York estimated that the average overall cost of
treating limb ischaemia with a graft was between £6,600 and £11,000,
depending on the site of the arterial blockage, while the cost of an amputation
was close to £11,000 [2].

Naftidrofuryl

This drug has been licensed for use in peripheral vascular disease since the
early 1970s at a dose of about 600 mg a day. A retrospective single-patient data
analysis of five randomised controlled studies has looked at its effectiveness
[3].
Bandolier
could find no other studies or reviews in the recent (post 1990) literature
apart from a single RCT which forms part of the review.

Readers should know that the work was sponsored by the manufacturer. The analysis
appears to be of high standard. The authors say that they:

made new case-record forms for all patients, with the data recorded by a
person with no knowledge about whether the treatment was active or placebo

included all demographic data, associated risk factors, and important
clinical measurements

included any critical events that occurred during the course of the study -
defined as local deterioration, a cardiovascular critical event (fatal or
non-fatal myocardial infarction, angina newly diagnosed, cerebrovascular
accident, transient ischaemic attack or sudden death), surgical interventions
(during the course of the study or immediately afterwards), and treatment
discontinuation.

included more patients than were in the original published studies to
obtain an "intention-to-treat" analysis, and all patients who were randomised
were included.

Studies

Five studies with 888 patients were included - 447 receiving naftidrofuryl and
441 placebo. They were double-blind parallel-group studies of three months (D1
and D2 in Germany) or 6 months duration (F1, F2 in France and GB in the UK).
Patients were usually men (85%); about 60% were smokers, 23% obese, 31% had
hypertension, 12% angina, 13% diabetes and 39% hyperlipidaemia. Patients in the
UK had the most severe disease and the shortest PFWD.
Bandolier
could find no mention of how exercise and smoking were handled.

Outcomes and results

Efficacy was assessed on three different measures.

Pain free walking distance

Treatment was considered successful if the patients completed the full treatment
period, were not lost to follow up and the PFWD increased by more than 50%. All
other outcomes were considered as failures.

Change in walking distance

This outcome examined the change in PFWD between the initial and
final assessments, or the last visit before treatment stopped in 834 patients in
whom this data was available. The analysis is shown in a L'Abbé plot for
individual trials. Points above the line of equality demonstrate a positive
effect of naftidrofuryl. In the paper, analysis of variance showed this to be
statistically significant.

Comment

This was a retrospective analysis of single-patient data, regarded as being an
excellent method. It did not claim to be a systematic search for all RCTs, but a
recent review of naftidrofuryl [4] failed to find any other studies which
approximated the stringent German guidelines for the assessment of
pharmacological interventions for peripheral arterial disease.

Pain-free walking distances are a proxy measurement for some features of the
illness. They may be a useful measure, because the increase ability to get about
enhances the activities of daily living and quality of life. Perhaps we haven't
found it yet, but there seems to be more research to be done, and good guidelines
on how to do it.

Stop smoking, keep walking

Stopping people smoking and giving them exercise training are known to be
beneficial, shown in a good systematic review [5].These are the mainstay of
conservative management of intermittent clausication [1]; controlled trials of
exercise increased PFWD by 88-190% in six studies, with little change in
non-excercise controls [5].

Pharmacological interventions that strengthen these beneficial effects may well
have its place. Systematic review of pentoxifylline also showed drug-related
benefits in walking distance [5. There is no cost-effectiveness data on which we
can draw [2], but the daily drug costs are about 60p.